Benzothiadiazine-1, 1-dioxides



United States Patent 3,210,346 BENZOTHIADIAZINE-l,l-DIOXIDES Lincoln Harvey Werner, Summit, and George de Stevens, New Providence, N .J., assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed July 12, 1961, Ser. No. 123,417 Claims. (Cl. 260243) The present invention concerns 3-cycloalkyl-lower alkyl-l,aA-benzothiadiazined,I-dioxides. More particu larly, it relates to compounds having one of the formulae 2 8 a, 7 NH RF- and in which the letter It stands for one of the whole num bers 1, 2, 3 and 4, R represents cycloalkyl having from three to eight carbon atoms as r-ing members, and R stands for hydrogen, halogeno, lower alkyl, trifluoromet-hyl and nitro, or salts of such compounds, as well as process for the preparation thereof.

The letter It stands primarily for 1, but may also represent one of the numbers 2, 3 and 4. The group of the formula -(C 2n) may, therefore, represent lower alkylene having from one to four carbon atoms, primarily methylene, as well as 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 2, 3-propylene, 1,3- propylene, 1,1-butylene, 1,-4-butylene and the like.

The cy-cloalkyl portion R has from three to eight, preferably from five to six, ring carbon atoms and is represented primarily by cyclopentyl and cyclohexyl, as well as by cyclopropyl, cyclobutyl, cycloheptyl and cyclooctyl. These cycloalkyl radicals are preferably unsubstituted, but may also have as substituents lower alkyl, e.g. methyl, ethyl, isopropyl and the like, attach-ed to ring carbon atoms, and represent, for example, 2-methylcyclopentyl, 3-methyl-cyclopentyl, 3-ethyl-cyclopentyl, 3-isopropyl-cyclopentyl, 4-methyl-cyclohexyl, 4-ethyl-cyclohexyl and the like.

The cycloal-kyl-lower alkyl radical having the formula -(C,,H )R may, therefore, be represented primarily by cycloalkylmethyl, in which cycloalkyl has from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethyl or cyclohexylmethyl, as well as cyclopropylmethyl, cyclobutyl-met-hyl, cycloheptylmethyl, cyclo-octy'lmethyl and the like, as well as 1-cycloalkyl ethyl, in which cycloalkyl has from three to eight, particularly from five to six, ring carbon atoms, e.g. l-cyclopentylethyl, l-cyclohexylethyl, l-cycloheptylethyl and the like, 2-cycloal-kylethyl, in which cycloalkyl has from three to eight, particularly from five to six, ring carbon atoms, e.g. 2-cyclopropylethyl, Z-cyclobutylethyl, 2-cyclopentylethyl, Z-cyclohexylethyl, 2-cycloheptylethyl and the like, or other cycloalkyl-lower alkyl radicals, in which cycloalkyl has from three to eight, particularly from five to six, ring carbon atoms and lower alkyl contains from three to four carbon atoms, e.g. l-cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 4-cyclopentylbutyl, l-cycloliexylpropyl, Lcyclohexylpropyl, 3-cyclohexylpropyl, 4- cyclohexylbutyl and the like.

3,210,346 Patented Oct. '5, 1965 ice The group R which is preferably attached to the 6- position or the 7-position of the 1,2,4-benzothiadiazine- 11,1-dioxide nucleus, may represent hydrogen, nitro or lower alkyl having from one to four carbon atoms, e.g. methyl, ethyl, n propyl, iso-propyl, n-butyl, secondary butyl, tertiary butyl and the like. However, R represents primarily trifluoromethyl or halogeno, especially halogeno having an atomic weight between 35 and 80, i.e. chloro or bromo, as well as fluoro and the like.

Salts of the compounds of this invention are primarily alkali metal, e.g. sodium, potassium and the like, or alkaline earth metal, e.g. magnesium, calcium and the like, salts thereof,

The compounds of this invention counteract the effect of physiological pressure agents, such as epinephrine, norepinephrine and hypertensive polypeptides, e.g. angiot-ensin-II-amide and the like, and thus cause a lowering of the blood pressure. They can, therefore, be used as antihypertensive agents to relieve hypertensive conditions, such as renal hypertension, essential hypertension, malignant hypertension and the like.

Particularly useful are the compounds having one of the formulae ing up the preparations there can be amployed substances which do not react with the new compounds, such as water, gelatinc, lactose, starches, stearic acid, magnesium .stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier used for pharmaceutical preparations. The latter may be in solid form, for example, as capsules, tablets, dragees and the like or in liquid form, for example, as solutions, suspensions, emulsions and the like. If necessary, these compositions may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, as well as salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances, particularly .antihypertensive agents, such as Rauwolfia alkaloids, e.g. reserpine, des-erpidine, rescinnamine and the like, semi-synthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, veratrum alkaloids, e.g. protoveratine A, protoveratine B and the like, synthetic antihypertensive drugs,

e.g. hydralazine, dihydralazine, guanethidine and the like,

ganglionic blockers, e.g. chlorisondamine and the like, or

any other useful substances, such' as potassium chloride or a Z-(N-acyl-sulfamyl)-N-(cycloalkyl-lower alkanoyl)- aniline, particularly a compound of the formula S O zNH-Ac R I in which n, R; and R have the previously-given meaning, and acyl, particularly the acyl radical of the formula Ac, stands for the acyl radical of an organic carboxylic acid, toform the desired 3-(cycIoaikyl-lower alkyl)-1,2,4-benzothiadiazine-l,1-dioxide compound, particularly a compound having one of the formulae in which n, R and R have the previously-given meaning, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting compound into a salt thereof.

The acylradical of an organic carboxylic acid, which substitutes the sulfamyl group, and which is represented in the above'formula by the radical Ac, is the acyl radical of a cycloalkyl-lower alkanoic acid and has more especially the formula CO-(C,,H )R in which n and R have the previously-given meaning. However, it may also stand for any other suitable acyl radical of an organic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic acid and the like.

Cyclization of the 2-sulfamyl-N-(cycloalkyl-lower alkanoyl)aniline is carried out at an elevated temperature, preferably at a temperature between 75 and 200. The cy clization may take place in the absence or in the presence of an inert solvent, such as, for example, ethanol, propanol, diethyleneglycol dimethylether, dimethylformamide and the like, if necessary, in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

The starting material used in the above procedure is new and is intended to be included within the scope of this invention. Particularly useful as starting materials are the compounds of the formula R so NH 2 2 orr,on,

R,' g-o-cm-cn (H,)...

urn-on,

in which in, R and R have the previously-given meaning.

The starting materials may be prepared, for example, by reacting a 2-sulfamyl-aniline,especially a compound of the formula,

A somm R: I

or a Z-(N-acyl-sulfamyl)-aniline, particularly a compound of the formula I NH;

in which R and Ac have the previously-given meaning, with the halide, particularly chloride, or the anhydride of a cycloalkyl-lower alkanoic acid, particularly an acid of the formula HOOC(C H )R in which n and R have the previously-given meaning. The acylation of the sulfamyl-nitrogen may taken place simultaneously with the desired acylation of the aniline-nitrogen. Whenever the treatment With the acylating reagent is carried out in the presence of an inert, slightly polar to non-polar organic solvent, such as an aromatic hydrocarbon, an ether and the like, the mono-acylated product, in which the aniline-nitrogen is acylated, is obtained. Any generated acid may be neutralized by adding a suitable reagent, e.g. sodium acetate and the like. Diacylation occurs whenever the acylation reagent is used in an excess amount and in the presence of a base, such as a tertiary amine, e.g. N,N,N-tri'ethylamine and the like, or a heterocyclic base,-e.g. pyridine and the like.

The compounds of this invention may also be prepared by reacting a 2-sulfamyl-aniline compound, particularly a compound "of the formula SOzNHg in which R has the previously-given meaning, with an ortho-ester, especially a lower alkyl ortho-ester, of a cycloalkyl-lower alkanoic acid, particularly an ortho-ester of the formula R-O R-O--(C 11 20-111 in which n and R have the previously-given meaning, and R represents lower alkyl, and, if desired, carrying out the optional steps.

As mentioned hereinbefore, an ortho-ester of a cycloalkyl-lower alkanoic acid is preferably a lower alkyl ortho-ester, in which lower alkyl (represented in the above formula by R) has from one to four carbon atoms and stands for methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; ethyl ortho-esters are the preferred reagents. The above reaction is preferably carried out at an elevated temperature, and in the presence of an inert organic solvent; if necessary, it may be performed in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

The resulting product may be obtained in the form of the free compound or as a salt thereof. A resulting metal, such as an alkali metal, salt may be converted into the free compound by treatment with an acidic reagent, such as an aqueous mineral acid, e.g. hydrochloric, sulfuric acid and the like. A resulting free compound may be converted into a metal, particularly into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in the presence of a suitable inert solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water and evaporating the solvent, or by reacting the free compound, for example, in an ether, e.g. p-dioxane, diethyleneglycol dimethyl-ether and the like, solution, with a metal, particularly an alkali metal, hydride or a metal, particularly an alkali metal, amide,

e.g. sodium hydride, potassium hydride, sodium amide, potassium amide and the like.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any state of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples illustrate the invention; they are not to be construed "as being limitations thereon. Temperatures are given in degrees Centigrade.

Example 1 A mixture. of 10.0 g. of 4-chloro-2-sulfamyl-aniline and 7.1 g. of cyclopentyl-acetic acid chloride in benzene containing 4.4 g. of sodium acetate is heated on the steam bath. The precipitate is filtered off and the benzene solution is evaporated to yield the desired 4-chloro- N-cyclopentylacetyl-2-sulfamyl-aniline. The latter is dissolved in N,N-dimethylformamide and the solution is refluxed for one hour. Water is added, and, upon chilling, the desired 7-chloro-3-cyclopentylmethyl-1,2,4-benzothiadiazine-1,1-dioxide having one of the formulae S NH CH2-C H, %ooH',-oH

N CH Hg and 2 s 01- N ca om em-0 g OH H;

precipitates, is collected and recrystallized from ethanol.

Example 2 A mixture of 4.0 g. of 5-chloro-2-sulfamyl-aniline and 2.8 g. of cyclopentyl-acetic acid chloride in a benzene solution containing 1.75 g. of sodium acetate, when reacted as shown in Example 1, yields the S-chloro-N- cyclopentylacetyl-2-sulfamyl-aniline, which is ring-closed to the desired 6-chloro-3-cyclopentylmethyl-1,2,4-benzothiadiazine-1,1-dioxide having one of the formulae by refluxing an N,N-dimethyl-formamide solution thereof.

Other compounds, such as, for example, the 6-chloro-3- cyclopropylmethyl 1,2,4 benzothiadiazine-l,1,-dioxide, 7 chloro-3-cyclobutylmethyl-1,2,4-benzothiadiazine-1,1- dioxide, 7 chloro-3-(l-cyclopentylethyl)-1,2,4-benzothiadiazine 1,1 dioxide, 7-chloro-3-(2-cyclopentylethyl) 1,2,4-benzothiadiazine-1,1-dioxide, 7-bromo-3-cyclopentyhnethyl 1,2,4 benzothiadiazine-1,1-dioxide, 3-cyclopentylmethyl 7 nitro-l,2,4-benZothiadiazine-1,l-dioxide, 3 cyclopentylmethyl-1,2,4-benzothiadiazine-1,1-dioxide, 3 cyclopentylmethyl-6-trifluoromethyl-1,2,4-benzothiadiazine 1,1 dioxide, 3-cyclopentylmethyl-7-tri- 6 fluoromethyl 1,2,4 benzothiadiazine-1,1-dioxide, 3-cyclopentylmethyl 6 methyl-1,2,4-benzothiadiazine-1,1- dioxide, 3 cyclopentylmethyl-7-methyl-1,2,4-benzothiadiazine 1,1 dioxide, 6-chloro-3-cyclohexylmethyl-1,2,4- benzothiadiazine 1,1 dioxide, 7-chloro-3-cyclohexylmethyl 1,2,4 benzothiadiazine-l,l-dioxide, 6-bromo-3- cyclohexylmethyl 1,2,4 benzothiadiazine-1,1-dioxide, 3 cyclohexylmethyl-6-trifiuoromethyl-1,2,4-benzothiadiazine 1,1 dioxide, 3-cyclohexylmethyl-7-trifluoromethyl 1,2,4 benzothiadiazine-1,1-dioxide, 7-chloro-3-(1-cyclohexylethyl) 1,2,4 benzothiadiazine-1,1-dioxide, 7- chloro- 3 cycloheptylmethyl-1,2,4-benzothiadiazine-1,1- dioxide, 6 chloro-3-cyclo-octylmethyl-1,2,4-benzothiadiazine 1,1 dioxide and the like, are prepared according to the previously-outlined procedure illustrated in the above examples.

Example 3 An aqueous solution of the sodium salt of 7-chloro-3- cyclopentylmethyl 1,2,4-benzo-thiadiazine-1,1-dioxide is prepared by dissolving 1.0 g. of 7-chloro-3-cyclopentylmethyl 1,2,4 benzothiadiazine-l,l-dioxide in a solution of an equivalent amount of sodium hydroxide in water.

What is claimed is:

1. A member selected from the group consisting of a compound having one of the formulae in which the letter In stands for an integer from 0 to 1, both inclusive, one of the groups R and R represents a member selected from the group consisting of chloro, bromo and trifiuoromethyl, and the other stands for hydrogen.

3. An alkali metal salt of a compound having one of the formulae and bromo and trifluoi'omethyl and the other stands for hydrogen.

4. 7 ehloro 3 cyclopentylmethyl 1,2,4 benzo- 1 thiadiazine 1,1 dioxide.

5. 6 chloro 3 oyclopentylmethyl 1,2,4 benz'othiadiazine 1,1 dioxide.

References Cited by the Examiner UNITED STATES PATENTS Petitcolas 260556 DAlelio et a1. 260-556 Gregory 260556 Randall et a1. 260556 Novello 260243 Novello 260-443 Topliss et al 260243 FOREIGN PATENTS Luxembourg.

OTHER REFERENCES Wertheirn; Textbook of Organic Chemistry, pages 763-4 NICHOLAS S. RIZZO, Primary Examiner. WALTER A. MODANCE, Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING ONE OF THE FORMULAE 